The main advantage of HDR-BT is its ability to deliver a relative high dose of radiation within a well-defined volume, with a rapid fall-off of dose outside the implanted area. This approach is ideal for the treatment of prostate cancer, where the gland lays very close to critical normal tissues, in particular the anterior rectal wall and bladder neck. Several retrospective studies with more than 5-year follow up have previously described the outcome of patients treated with combination of EBRT and HDR-BT [7, 15,16), but data from prospective randomized trail comparing results of this combination with dose escalation RT3D or IMRT is still missing.
To our knowledge, this is the first paper that explores the ability of 3DHDR on impacting in the final results. The use of 3DHDR was significantly related to the bC rates, in both uni and multivariate analysis (p< 0.001). Based in the use of 3D planning Martin et al. described this same strategy to enable real time distribution of the isodose in all CT slices, observing an increase accuracy of the delivery of the prescribed dose.
There is clinical evidence that suggests that prostate tumors contain a low proportion of proliferating cells, having a lower α/β ratio than the other epithelial tumors, in the range of 1.2–2.5 17, 18
. We assumed, for BED calculation purposes a α/β ratio of 1.5 Gy for tumor and no correction for tumor repopulation in the interval between fractions was performed. The BED was calculated assuming a α/β ratio of 1.5 for PCa. The median BED for EBRT (BED-RT) was 104 Gy1.5
(range 84-118.8 Gy1.5
) and for HDR-BT (BED-HDR) was 76 Gy1.5
(range 58.7-120 Gy1.5
). The total BED (BED-TT) ranged from 142.7 Gy1.5
to 236.7 Gy1.5
with a median of 180 Gy1.5
The total BED (BED-TT) ranged from 142.7 Gy1.5
to 236.7 Gy1.5
. We observed a trend toward to a better bC rate for all risk groups when a BED-TT higher than 185 Gy1.5
was administered (p< 0.001). Similarly, a study by Tang et al. 19
evaluated results of 88 patients treated with EBRT alone (66 Gy) and EBRT (46 Gy) combined to HDR-BT (16 Gy to 20 Gy), the same dose levels e observed in this study, but with no NAAD was allowed in that group of patients. For the HDR-BT cohort, the overall actuarial 5-year bC was 67.4%. They noted a significant advantage (p= 0.011) when BED calculations were used to compare results of HDR-BT associated to EBRT. They have also compared the results in terms of HDR-BT total dose, 16 Gy versus 20 Gy, observing that the 5-year bC rates, using the RTOG-ASTRO Phoenix definition, were 58.8% and 77.3%, respectively (p= 0.07). In our analysis the bC rates had a statistical significant difference when total HDR-BT doses administered were < 20 Gy (79.8%) and ≥ 20Gy (86.3%), p< 0.001. We can also observe that the dose level of 66 Gy given in 33 fractions has a considerable inferior BED value than the same nominal total dose given by 46 Gy in 23 fractions and 20 Gy given in 4 fractions of HDR-BT. Our results in terms of dose levels of HDR-BT for the different RG have shown an improvement in bC with HDR dose escalation, with a trend toward better bC rates when BED-TT dose over 180 Gy1.5
was administered (p< 0.001).
Galalae et al 20
also investigated the long-term outcome by GR using HDR-BT and EBRT with or without NAAD. There were 611 patients grouped as follows: 46 patients into LR, 188 patients into IR and 359 patients considered HR. Using the ASTRO definition for BF they observed that the actuarial bC and disease free survival rates at 5-year and 10-year were 77%, 67%, 73% and 49%, respectively. For the different RG the actuarial 5-year bC rates were 96% for LR, 88% for IR and 69% for HR. They observed that GS and GR were statistical significant predictive factors of bC, what we also confirmed in the present study, were GS (p= 0.002) and RG (p= 0,040) were statistical significant predictive factors for BF. They observed that CS and iPSA were also statistical significant predictive factors, what was not confirmed in this study.
Deger et al. 21
evaluated 422 patients with localized prostate cancer treated between 1992 and 2001 with HDR-BT and 3DRT. All patients underwent laparoscopic pelvic lymph node dissection to exclude patients with lymphatic involvement. The BF was also defined according to the ASTRO criteria. The bC according to RG were 100% T1, 75% for T2 and 60% T3 at 5 years. Five-year bC were 81% in the LR, 65% in the IR and 59% in the HR. Five-year OS and bC were 87% and 94%, respectively. They also observed that iPSA, RG and age were significantly related to bC. In our study the use of NAAD was not associated with better bC (p= 0.425). When the patients were grouped according to the of BF and use of NAAD, there was not a statistical significance for a better bC related to the its use (p=0.604).
There are a scarce number of papers that have published the results of HDR-BT and EBRT for PCa using the RTOG-ASTRO Phoenix definition. This definition states that “To avoid the artifacts resulting from short follow-up, the reported date of control should be listed as 2 years short of the median follow-up” 12
. Chin et al. 22
published the results of 65 consecutive patients treated between 1998 and 2004 with combination of EBRT and HDR-BT given in 2 fractions. Sixty patients (92.3%) were considered IR or HR. With a median follow-up of 3.5 years (range 0.6-5.8), two patients had died of metastatic disease and other four patients had BF, giving a 3-year actuarial bC rate of 90.8%. Yamada et al. 23
also reported the results of 105 patients consecutively treated between 1998 and 2004 with EBRT (45-50.4 Gy) and HDR-BT (5.5-7.0 Gy per fraction). With a median follow-up of 44 months (8-79 months), the actuarial 5-year bC rates for LR, IR and HR were 100%, 98%, and 92%, respectively. In the current study the actuarial bC rates at 5-year were 91.8% for LR group, 79.3% for IR group and 69.1% for HR group (p= 0.040), respectively.
Patients considered HR have more chances of BF. This phenomenon could be a consequence of current inadequate imaging of lymph node or bone metastasis or due subclinical metastatic spread that remains undetectable during radical treatment. However, tumor biology itself could lead to the progression of the disease in the HR group. As a consequence, risk-adapted therapy is very important in these cases. The combination of EBRT and HDR-BT is an alternative strategy of dose escalation that can potentially achieve an even higher BED given to the tumour when compared 3DRT or IMRT, but for patients at HR the localized dose given by HDR-BT may be a potential disadvantage, because a microscopic spread outside the prostate and even its capsule may exist. In these cases, the combination of HDR-BT and EBRT can provide treatment to potential areas of microscopic spread. What is still not answered is if adding pelvic radiation, instead to localized EBRT in combination to HDR-BT for PCa patients with a more than 15% risk of positive lymph nodes will really improve outcome, and is stil controversial in literature 24
A hundred and six (50.7%) patients had no NAAD in our analysis. Despite being a retrospective analysis, the patients were well balanced when having or not NAAD into the RG as seem in table . The use of NAAD is also still controversial for patients with IR to HR. Martinez et al. 25
in a study of 1,260 patients treated with pelvic EBRT and HDR-BT observed similar OS, DFS and bC for patients who were treated with or without the addition of a course of NAAD up to 6 months prior to radiation. They observed that NAAD did not confer a therapeutic advantage, and instead of that added side effects and cost. Furthermore, for the most unfavourable group, there was a higher rate of distant metastasis and more prostate cancer-related deaths. We could not observe a statistical significant benefit on BC rates with the use of NAAD in none of the GR.
Vargas et al. 26
performed a matched-pair analysis of patients treated with combined EBRT and HDR-BT from January 1993 to March 2003. A total of 1432 were evaluated. There were 755 cases identified as having a risk of pelvic limphonodes positive of more than 15% using the Roach formula. Of these, 255 cases were treated without pelvic EBRT and randomly matched by GS, CS and iPSA to 500 cases treated with pelvic EBRT, resulting in 250 pairs. As results they observed that BF, and OS were not significantly different for patients treated with pelvic radiotherapy. At a median follow-up of 4 years the bC and OS rates were 78%, 86%, 89% and 88%, respectively. In our analysis, the actuarial 5- and 10-year OS were 95.7% and 90.6%, while the actuarial bC rates at 5- and 10-year for the different RG were 91.8% and 82.3% for LR, 79.3% and 67.7% for IR, and 68.5% and 41.3% for HR (p= 0.040), respectively.
Our results and others suggested that bC is related not just clinical characteristics of patients, as RG and GS, but it is also related to treatment parameters as total dose of HDR-BT and BED. To our knowledge, this is the first paper that found a positive relationship between the quality of planning and the outcome.
So far in our own experience, HDR-BT associated to EBRT is a successful form of treatment of PCa, with results comparable to published data, results that tend to be even better with the introduction of image guided brachytherapy.
In conclusion, dose escalation, evaluated through BED, and 3DHDR are predictive factors for bC, as well as other already accepted factors described in literature as GS and RG. The challenges for the future are to determine which treatment option will have the best result for each patient and the role of NAAD when using EBRT combined to HDR-BT for IR and HR patients.